Feedback loop and crosstalk in the mTORC1/2 signaling network

mTORC1/2 信号网络中的反馈环路和串扰

基本信息

  • 批准号:
    10424504
  • 负责人:
  • 金额:
    $ 35.85万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-07-01 至 2024-06-30
  • 项目状态:
    已结题

项目摘要

Project Summary Deciphering feedback control and crosstalk between signaling molecules is critical to understand not only the mechanisms of cell growth/survival but also drug resistance in therapies. mTOR is regarded as one of the primary regulators of cellular fates by sensing and integrating cues from the cellular environment such as nutrients, energy, and stress. Thus, dysregulation of mTOR plays critical roles in the progression of diseases such as cancer, diabetes, and neurological disorders. Feedback signaling from mTOR has been of great interest as this suggests the major mechanisms by which cells adapt to the environmental stress and resist to drug treatment for their growth, proliferation, and survival. Many studies have focused on feedback signaling after partial mTOR complex 1 (mTORC1) inhibition by rapamycin, or knockout or knockdown of components in mTOR complexes. However, the feedback responses to mTOR kinase inhibition or suppression of both mTORC1/2 are not known. Because of the significant importance of mTOR feedback and crosstalk signaling, we have established a robust system to gain deep insight into the rewired signaling which determines cells’ survival and death strategies. Although it is generally believed that mTORC1/2 targeting will be a very promising tumor treatment, our studies using proteomics, metabolomics, glycomics, and biochemical/cellular methods reveal that dual mTORC1/2 inhibition leads to feedback activation of growth/survival signaling through integrin/ focal adhesion kinase/ insulin- like growth factor receptor signaling networks. Unexpectedly, mTORC1/2 suppression also mediates activation of Akt, one of the strongest survival kinase, by increasing phosphorylation at both its hydrophobic motif and turn motif. Considering the current paradigm that mTORC2 is the major kinase responsible for Akt phosphorylation at its hydrophobic motif, mTORC2-independent Akt activation in resistant cells highlights modification of the current paradigm that is extremely important for the successful clinical application of mTOR inhibitors. Also, surprisingly, the resistant cells increase migratory/invasive potential when mTORC1/2 is blocked. To elucidate our unexpected, but clinically pivotal observations, our specific aims are to determine the feedback activation mechanisms and crosstalk in mTOR signaling networks with focuses on 1) determining central molecules or pathway for mTORC2-independent Akt activation, 2) mechanisms by which cells induce cap-independent translation of survival factors and 3) mechanisms by which cells increase migratory and invasive potential following mTORC1/2 inhibition. Our proposed research is of therapeutic significance in that it will contribute to the deep understanding of why and how certain types of cells are sensitive, but other types are resistant to mTORC1/2 targeting, which will provide the basis for personalized medicine. Our study will also provide novel targets for which resistant tumor types can be treated with combinatorial drug treatments to be able to manage these tumors effectively. Thus, we expect that our study will provide a strong foundation to help develop successful mTORC1/2-targeted therapies.
项目摘要 破译信号分子之间的反馈控制和串扰不仅对于理解 细胞生长/存活的机制,以及治疗中的耐药性。MTOR被认为是主要的 通过感知和整合来自细胞环境的线索来调节细胞命运,例如营养物质, 精力和压力。因此,mTOR的失调在疾病的发展中起着关键作用,例如 癌症、糖尿病和神经疾病。来自mTOR的反馈信号引起了人们的极大兴趣,因为 提示细胞适应环境压力和抵抗药物治疗的主要机制 它们的生长、繁殖和生存。许多研究都集中在部分mTOR后的反馈信号 化合物1(MTORC1)被雷帕霉素抑制,或敲除或敲除mTOR复合体中的成分。 然而,对mTOR激酶抑制或同时抑制mTORC1/2的反馈反应尚不清楚。 由于mTOR反馈和串扰信号的重要性,我们已经建立了一个健壮的 系统,以深入了解重新连接的信号,它决定了细胞的生存和死亡策略。 尽管人们普遍认为mTORC1/2靶向将是一种非常有前途的肿瘤治疗方法,但我们的研究 利用蛋白质组学、代谢组学、糖组学和生化/细胞方法揭示双重mTORC1/2 抑制通过整合素/粘着斑激酶/胰岛素反馈激活生长/生存信号- 比如生长因子受体信号网络。出乎意料的是,mTORC1/2抑制也介导了激活 通过增加Akt的疏水基序和TURN的磷酸化,使Akt成为最强的生存激酶之一 Motif。考虑到目前的范式,mTORC2是负责Akt磷酸化的主要激酶 在其疏水基序中,耐药细胞中不依赖于mTORC2的Akt激活突出了对 目前的范例对于mTOR抑制剂的成功临床应用极其重要。另外, 令人惊讶的是,当mTORC1/2被阻断时,耐药细胞增加了迁移/侵袭的可能性。为了澄清 我们意想不到的,但临床上关键的观察,我们的具体目标是确定反馈激活 MTOR信令网络中的机制和串扰,重点在于1)确定中心分子或 MTORC2非依赖Akt激活的途径,2)细胞诱导帽非依赖的机制 生存因子的翻译和3)细胞增加迁移和侵袭潜能的机制 在mTORC1/2抑制后。我们提议的研究具有治疗意义,因为它将有助于 对某些类型的细胞为什么以及如何敏感,但其他类型的细胞对 MTORC1/2靶向,这将为个性化用药提供基础。我们的研究也将为我们提供新的 耐药肿瘤类型可以用组合药物治疗的靶点能够管理 这些肿瘤有效地。因此,我们期待我们的研究将提供坚实的基础,以帮助开发 成功的mTORC1/2-靶向治疗。

项目成果

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Sang-Oh Yoon其他文献

Sang-Oh Yoon的其他文献

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{{ truncateString('Sang-Oh Yoon', 18)}}的其他基金

Feedback loop and crosstalk in the mTORC1/2 signaling network
mTORC1/2 信号网络中的反馈环路和串扰
  • 批准号:
    10651817
  • 财政年份:
    2019
  • 资助金额:
    $ 35.85万
  • 项目类别:
Feedback loop and crosstalk in the mTORC1/2 signaling network
mTORC1/2 信号网络中的反馈环路和串扰
  • 批准号:
    10194420
  • 财政年份:
    2019
  • 资助金额:
    $ 35.85万
  • 项目类别:
Feedback loop and crosstalk in the mTORC1/2 signaling network
mTORC1/2 信号网络中的反馈环路和串扰
  • 批准号:
    9797783
  • 财政年份:
    2019
  • 资助金额:
    $ 35.85万
  • 项目类别:

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